Hepatic steatosis (fatty liver) progresses to steatohepatitis in only a small proportion of individuals. The risk factors that lead to progression are uncertain, but studies suggest that in some cases steatohepatitis is linked to a defect in hepatic triglyceride (TG) secretion. Hepatic TG secretion can be blocked in mice by feeding a diet devoid of methionine and choline (methionine-choline-deficient;MCD);when such a formula is administered together with excess sucrose, it provokes severe steatohepatitis. Preliminary data from our laboratory indicate that a sucrose-rich MCD formula causes hepatocellular apoptosis in vivo. This phenomenon is reminiscent of "lipoapoptosis" that has been described previously in other organs. In this application, we test the hypothesis that dietary sucrose provokes lipoapoptosis in susceptible mice and leads to steatohepatitis. Aim 1 is designed to confirm that lipoapoptosis takes place in the livers of MCD mice and document the importance of dietary sucrose to the pathogenesis of MCD steatohepatitis. Separate experiments will address whether dietary sucrose also induces lipoapoptosis in other mice that have related but independent defects in hepatic TG secretion (MTP-deficient;Scd-1-deficient). Aim 2 will investigate the importance of lipoapoptosis relative to lipid peroxidation in the pathogenesis of MCD steatohepatitis. Of particular interest is whether lipoapoptosis and lipid peroxidation are independent causes of liver injury or lipid peroxidation follows lipoapoptosis. Aim 3 concentrates on the mechanism by which saturated fatty acids cause hepatocyte apoptosis. Experiments will address whether fatty acid toxicity is due primarily to de novo synthesis of ceramide or to disruption of mitochondria with activation of an apoptosis cascade. Overall, the proposed work highlights lipoapoptosis as a potentially important cause of steatohepatitis in individuals with impaired hepatic TG secretion. Because lipoapoptosis can be regulated by dietary nutrients, some individuals at risk of steatohepatitis may be able to reduce their risk by modifying their diet.